8G2T

CRYSTAL STRUCTURE OF THE KPC-2 D179N VARIANT IN COMPLEX WITH RELEBACTAM (IMINE HYDROLYSIS INTERMEDIATE)

8G2T の概要

• エントリーDOI: 10.2210/pdb8g2t/pdb
• 関連するPDBエントリー: 8G2R
• 分子名称: Carbapenem-hydrolyzing beta-lactamase KPC, (2S,5R)-5-amino-1-formyl-5-hydroxy-N-(piperidin-4-yl)piperidine-2-carboxamide, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: beta-lactamase, inhibitor, antibiotic resistance, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28541.05

構造登録者

Alsenani, T.,van den Akker, F. (登録日: 2023-02-06, 公開日: 2023-08-09, 最終更新日: 2024-11-20)

主引用文献

Alsenani, T.A.,Viviani, S.L.,Papp-Wallace, K.M.,Bonomo, R.A.,van den Akker, F.
Exploring avibactam and relebactam inhibition of Klebsiella pneumoniae carbapenemase D179N variant: role of the Omega loop-held deacylation water.
Antimicrob.Agents Chemother., 67:e0035023-e0035023, 2023

PubMed Abstract: carbapenemase-2 (KPC-2) presents a clinical threat as this β-lactamase confers resistance to carbapenems. Recent variants of KPC-2 in clinical isolates contribute to concerning resistance phenotypes. expressing KPC-2 D179Y acquired resistance to the ceftazidime/avibactam combination affecting both the β-lactam and the β-lactamase inhibitor yet has lowered minimum inhibitory concentrations for all other β-lactams tested. Furthermore, expressing the KPC-2 D179N variant also manifested resistance to ceftazidime/avibactam yet retained its ability to confer resistance to carbapenems although significantly reduced. This structural study focuses on the inhibition of KPC-2 D179N by avibactam and relebactam and expands our previous analysis that examined ceftazidime resistance conferred by D179N and D179Y variants. Crystal structures of KPC-2 D179N soaked with avibactam and co-crystallized with relebactam were determined. The complex with avibactam reveals avibactam making several hydrogen bonds, including with the deacylation water held in place by Ω loop. These results could explain why the KPC-2 D179Y variant, which has a disordered Ω loop, has a decreased affinity for avibactam. The relebactam KPC-2 D179N complex revealed a new orientation of the diazabicyclooctane (DBO) intermediate with the scaffold piperidine ring rotated ~150° from the standard DBO orientation. The density shows relebactam to be desulfated and present as an imine-hydrolysis intermediate not previously observed. The tetrahedral imine moiety of relebactam interacts with the deacylation water. The rotated relebactam orientation and deacylation water interaction could potentially contribute to KPC-mediated DBO fragmentation. These results elucidate important differences that could aid in the design of novel β-lactamase inhibitors.

PubMed: 37750722
DOI: 10.1128/aac.00350-23

実験手法

X-RAY DIFFRACTION (1.26 Å)